This invention relates to tetrahydroquinoline compounds or pharmacologically acceptable salts thereof which have a specific and strong binding affinity for androgen receptors and exhibit androgen receptor agonism or antagonism, and pharmaceutical compositions containing the compounds or their pharmacologically acceptable salts.
Androgens are a generic name for C19 steroids. They are sex hormones important for the normal sexual differentiation and growth of males, masculinization at puberty, activation of initial spermatogenesis in the testes, and maintenance of male function. About 90% of androgens are produced by Leydig cells of the testes, the remaining 10% by the adrenal gland, mainly as testosterone, and secreted into the blood. Testosterone is taken up into target cells, and converted by 5xcex1-reductase into dihydrotestosterone (DHT) with potent biological activity. DHT, as well as testosterone, plays an important role in the development of male secondary sex characteristics (growth of sebaceous glands, acne, development of body hair, voice deepening, development of beards), growth of external genitalia (penis, testis), growth of sex accessory organs (prostate, seminal vesicles), sexual stimuli, and occurrence of erection.
In addition to these major actions, androgens have actions other than those on the reproductive system, such as protein anabolic action (increases in skeletal muscles and bone mass), suppression of gonadotropin secretion, and acceleration of erythropoiesis promoting action. Target cells for androgens are localized in external and sex accessory tissues, and are widely distributed in the brain, pituitary gland, muscular tissues, bones, and kidneys (N. Engl. J. Med. 334, 707-714, 1996).
In addition to these roles, androgens are reported to show an anti-inflammatory action. Nowadays, it is becoming clear that androgens attenuate arthritis and autoimmune disease by inhibiting the proliferation of inflammatory cells or suppressing the production of cytokines such as IL-6 (Ann. Rheum. Dis. 55, 811-815, 1996).
All androgenic actions are mediated through androgen receptor (hereinafter referred to as AR) having a molecular weight of about 100,000 which is present in the nuclei of target cells. The gene of AR was cloned by Chang and Lubahn et al. in 1988. Their study demonstrated that AR has a similar structure to estrogen, progesterone, mineral corticoid, and glucocorticoid receptors, and they build a nuclear steroid receptor family (Science 240, 324-326, 327-330, 1988). Androgens with high liposolubility penetrate the target cell membrane by passive diffusion, and bind to the hormone-binding region of AR specifically and with high affinity to form dimers, which bind to an androgen responsive DNA region (androgen response element: ARE) localized upstream from a particular gene. As a result, transcription of the target gene is initiated to induce the expression of mRNA, thereby producing a functional protein responsible for an androgenic action, thus exhibiting this action (Trend in Endocrinology and Metabolism 9, 317-324, 1998). In connection with this mechanism, compounds which bind to AR and show the same actions as natural ligands such as testosterone are defined as agonists, while compounds which inhibit their action are named antagonists.
As the AR agonists, androgen steroid preparations, such as testosterone esters and their derivatives, are currently used in the treatment of male hypogonadism, wasting diseases (malignant tumor, trauma, chronic renal disease, burns), and osteoporosis.
However, these androgen steroid preparations can cause side effects inherent in steroid preparations, such as hepatic dysfunction and gastrointestinal disorder, and may develop androgen-dependent tumor (e.g. prostatic cancer) or prostatic hypertrophy, or aggravate symptoms of these diseases, because they act excessively on the prostate if used in male patients, especially in elderly patients. If these preparations are administered to female patients, they pose major problems of virilizing actions, such as changes in the vocal cord (male-like hoarseness), hypertrichosis of the body trunk, alopecia and acne.
Hence, nonsteroidal AR agonists, which do not show excessive action on the prostate and are minimal in side effects, are desired for the treatment of hypogonadism, and have been under research and development. However, no compounds recognized throughout the world have been created.
For the treatment of wasting disease and osteoporosis, the desired AR agonists are those which do not show excessive action on the prostate, but exhibit potent AR agonism toward skeletal muscle tissue and bone tissue. However, such compounds have not been created.
As AR antagonists, steroidal anti androgen preparations, such as chlormadinone acetate and cyproterone acetate, which are gestagen derivatives, have been used as therapeutic agents. It has been pointed out, however, that these steroid preparations accelerate the negative feedback mechanism of the hypothalamic-pituitary axis by their progesterone action, thereby lowering the blood testosterone level and decreasing sexual function and libido (Drugs Aging 5, 59-80, 1994).
Thus, AR antagonists, as nonsteroidal synthetic compounds diminished in the side effects of the steroids, are desired.
The present invention has been accomplished in view of the therapies of and therapeutic researches on the diseases mediated through AR. The objects of the present invention are to provide novel nonsteroidal compounds and pharmacologically acceptable salts thereof, which are free from the side effects observed with androgen steroid preparations, have a specific and strong binding affinity for AR and exhibit AR agonism or antagonism; and to provide pharmaceutical compositions comprising these compounds or salts as active ingredients.
The inventors of the present invention conducted in-depth studies in an attempt to attain the above objects. As a result, they have found that tetrahydroquinoline compounds of the following formula (I) (hereinafter referred to as xe2x80x9ccompounds of the present inventionxe2x80x9d) have AR agonism or antagonism, have excellent therapeutic effects on AR-mediated diseases, particularly by not acting excessively on the prostate as AR agonists but by showing potent action on skeletal muscle tissue and bone tissue. Based on these findings, they have accomplished this invention.
That is, the present invention relates to a tetrahydroquinoline compound represented by the following formula (I) or pharmacologically acceptable salts thereof: 
wherein R1 and R2 each independently represent a hydrogen atom, an alkyl group having 1-9 carbon atoms, an alkoxy group having 1-9 carbon atoms, a halogen atom, a nitro group, xe2x80x94NR5R6 (wherein R5 and R6 each independently represent a hydrogen atom, an alkyl group having 1-9 carbon atoms, a cycloalkyl group having 3-7 carbon atoms, an aralkyl group having 7-9 carbon atoms which may optionally be substituted by one or more members selected from the group consisting of an alkyl group having 1-9 carbon atoms, an alkoxy group having 1-9 carbon atoms, a halogen atom and a nitro group, an aryl or heteroaryl group which may optionally be substituted by one or more members selected from the group consisting of an alkyl group having 1-9 carbon atoms, an alkoxy group having 1-9 carbon atoms, a halogen atom and a nitro group, a formyl group, an aliphatic acyl group having 2-5 carbon atoms, an aliphatic acyloxy group having 2-5 carbon atoms, an aromatic acyl group, an alkylsulfonyl group having 1-4 carbon atoms, an arylsulfonyl group, an alkoxycarbonyl group having 2-5 carbon atoms, a hydroxyoxalyl group, or an alkoxyoxalyl group having 3-7 carbon atoms), a carboxyl group, an alkoxycarbonyl group having 2-5 carbon atoms, an amido group, an alkylamido group having 2-5 carbon atoms, an alkylthio group having 1-4 carbon atoms, an alkylsulfinyl group having 1-4 carbon atoms, an alkylsulfonyl group having 1-4 carbon atoms, a cyano group, a sulfamoyl group, an alkylsulfamoyl group having 1-4 carbon atoms, an amidino group, or an alkyl or alkoxy group having 1-5 carbon atoms which has been substituted by fluorine atom(s);
X represents xe2x80x94Oxe2x80x94, xe2x80x94OCOxe2x80x94, xe2x80x94OSO2xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SCOxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR7xe2x80x94, xe2x80x94NR7COxe2x80x94, xe2x80x94NR7SO2xe2x80x94, xe2x80x94NR7CONHxe2x80x94, xe2x80x94NR7CSNHxe2x80x94, xe2x80x94NR7COOxe2x80x94 or xe2x80x94NR7COCOxe2x80x94 (wherein R7 represents a hydrogen atom, an alkyl group having 1-9 carbon atoms, a cycloalkyl group having 3-7 carbon atoms, an aralkyl group having 7-9 carbon atoms which may optionally be substituted by one or more members selected from the group consisting of an alkyl group having 1-9 carbon atoms, an alkoxy group having 1-9 carbon atoms, a halogen atom, and a nitro group, an alkoxyalkyl group having 2-5 carbon atoms, or an aryl or heteroaryl group which may optionally be substituted by one or more members selected from the group consisting of an alkyl group having 1-9 carbon atoms, an alkoxy group having 1-9 carbon atoms, a halogen atom, and a nitro group);
R3 represents a hydrogen atom, an alkyl group having 1-9 carbon atoms, a cycloalkyl group having 3-7 carbon atoms, an aralkyl group having 7-9 carbon atoms which may optionally be substituted by one or more members selected from the group consisting of an alkyl group having 1-9 carbon atoms, an alkoxy group having 1-9 carbon atoms, a halogen atom, and a nitro group, an alkoxyalkyl group having 2-5 carbon atoms, or an aryl or heteroaryl group which may optionally be substituted by R8 (wherein R8 represents an alkyl group having 1-9 carbon atoms, an alkoxy group having 1-9 carbon atoms, a halogen atom or a nitro group), provided that when X is NR7, R3 and R7 may, together with the nitrogen atom to which they are bonded, form a 3- to 6-membered cyclic amino group or a 4- to 10-membered cyclic imido group;
Y represents an alkylene group having 1-9 carbon atoms which may optionally be substituted by alkyl group(s) having 1-9 carbon atoms, cycloalkyl group(s) having 3-7 carbon atoms, hydroxyl group(s), alkoxy group(s) having 1-9 carbon atoms or xe2x80x94NR9R10 (wherein R9 and R10 each independently have the same meaning as R5);
Z represents a single bond, xe2x80x94Oxe2x80x94, xe2x80x94OCOxe2x80x94, xe2x80x94OSO2xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SCOxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR11xe2x80x94, xe2x80x94NR11COxe2x80x94, xe2x80x94NR11SO2xe2x80x94, xe2x80x94NR11CONHxe2x80x94, xe2x80x94NR11CSNHxe2x80x94, xe2x80x94NR11COOxe2x80x94 or xe2x80x94NR11COCOxe2x80x94 (wherein R11 represents a hydrogen atom, an alkyl group having 1-9 carbon atoms, a cycloalkyl group having 3-7 carbon atoms, an aralkyl group having 7-9 carbon atoms which may optionally be substituted by one or more members selected from the group consisting of an alkyl group having 1-9 carbon atoms, an alkoxy group having 1-9 carbon atoms, a halogen atom, and a nitro group, an alkoxyalkyl group having 2-5 carbon atoms, or an aryl or heteroaryl group which may optionally be substituted by R12 (wherein R12 is an alkyl group having 1-9 carbon atoms, an alkoxy group having 1-9 carbon atoms, a halogen atom, a nitro group, an aryl or heteroaryl group which may optionally be substituted by one or more members selected from the group consisting of an alkyl group having 1-9 carbon atoms, an alkoxy group having 1-9 carbon atoms, a halogen atom, and a nitro group, xe2x80x94NR13R14 (wherein R13 and R14 each independently have the same meaning as R5), a carboxyl group, an alkoxycarbonyl group having 2-5 carbon atoms, an amido group, an alkylamido group having 2 -5 carbon atoms, an alkylthio group having 1-4 carbon atoms, an alkylsulfinyl group having 1-4 carbon atoms, an alkylsulfonyl group having 1-4 carbon atoms, a cyano group, a sulfamoyl group, an alkylsulfamoyl group having 1-4 carbon atoms, or an alkyl or alkoxy group having 1-5 carbon atoms which has been substituted by fluorine atom(s))); and
R4 represents a hydrogen atom, an alkyl group having 1-9 carbon atoms, a cycloalkyl group having 3-7 carbon atoms, an aralkyl group having 7-9 carbon atoms which may optionally be substituted by one or more members selected from the group consisting of an alkyl group having 1-9 carbon atoms, an alkoxy group having 1-9 carbon atoms, a halogen atom, and a nitro group, an alkoxy group having 1-9 carbon atoms, an alkoxyalkyl group having 2-5 carbon atoms, a halogen atom, a silyl group substituted by hydrocarbon group(s), or an aryl or heteroaryl group which may optionally be substituted by R15 (wherein R15 independently has the same meaning as R12), provided that when Z is other than a single bond, R4 is not a halogen atom. The present invention also relates to a pharmaceutical composition, and an androgen receptor modulator, each comprising the tetrahydroquinoline compound of the formula (I) or pharmacologically acceptable salts thereof as the active ingredient.
The substituents in the formula (I) will be described.
Examples of the xe2x80x9calkyl group having 1-9 carbon atomsxe2x80x9d are straight chain or branched chain alkyl groups, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a sec-butyl group, an n-pentyl group, a tert-amyl group, a 3-methylbutyl group, a neopentyl group, an n-hexyl group, a 3,3-dimethylbutyl group, a 2-ethylbutyl group, an n-heptyl group, a 2-methylhexyl group, an n-octyl group, a 2-propylpentyl group, and an n-nonyl group.
Examples of the xe2x80x9calkoxy group having 1-9 carbon atomsxe2x80x9d are straight chain or branched chain alkoxy groups, such as a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a tert-butoxy group, a sec-butoxy group, an n-pentyloxy group, a tert-amyloxy group, a 3-methylbutoxy group, a neopentyloxy group, an n-hexyloxy group, a 3,3-dimethylbutoxy group, a 2-ethylbutoxy group, an n-heptyloxy group, a 2-methylhexyloxy group, an n-octyloxy group, a 2-propylpentyloxy group, and an n-nonyloxy group.
Examples of the xe2x80x9chalogen atomxe2x80x9d are a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
Examples of the xe2x80x9ccycloalkyl group having 3-7 carbon atomsxe2x80x9d are a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group.
Examples of the xe2x80x9caralkyl group having 7-9 carbon atomsxe2x80x9d are a benzyl group, a phenethyl group, and a phenylpropyl group.
Examples of the substituted aralkyl group having 7-9 carbon atoms in the xe2x80x9caralkyl group having 7-9 carbon atoms which may optionally be substitutedxe2x80x9d include a 4-fluorobenzyl group.
Examples of the xe2x80x9caryl groupxe2x80x9d are a phenyl group, a 1-naphthyl group, and a 2-naphthyl group.
Examples of the substituted aryl group in the xe2x80x9caryl group which may optionally be substitutedxe2x80x9d include a 4-nitrophenyl group, a 4-fluorophenyl group, and a 2,5-difluorophenyl group.
Examples of the xe2x80x9cheteroaryl groupxe2x80x9d are a furyl group, and a pyridyl group.
Examples of the xe2x80x9caliphatic acyl group having 2-5 carbon atomsxe2x80x9d are straight chain or branched chain aliphatic acyl groups, such as an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, an isovaleryl group, and a pivaloyl group.
Examples of the xe2x80x9caliphatic acyloxy group having 2-5 carbon atomsxe2x80x9d are straight chain or branched chain aliphatic acyloxy groups, such as an acetoxy group, a propionyloxy group, a butyryloxy group, an isobutyryloxy group, a valeryloxy group, an isovaleryloxy group, and a pivaloyloxy group.
Examples of the xe2x80x9caromatic acyl groupxe2x80x9d are a benzoyl group and a toluoyl group.
Examples of the xe2x80x9calkylsulfonyl group having 1-4 carbon atomsxe2x80x9d are straight chain or branched chain alkylsulfonyl groups, such as a methanesulfonyl group, an ethanesulfonyl group, an n-propylsulfonyl group, an isopropylsulfonyl group, an n-butylsulfonyl group, an isobutylsulfonyl group, a tert-butylsulfonyl group, and a sec-butylsulfonyl group.
Examples of the xe2x80x9carylsulfonyl groupxe2x80x9d are a benzenesulfonyl group and a toluenesulfonyl group.
Examples of the xe2x80x9calkoxycarbonyl group having 2-5 carbon atomsxe2x80x9d are straight chain or branched chain alkoxycarbonyl groups, such as a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an isopropoxycarbonyl group, an n-butoxycarbonyl group, an isobutoxycarbonyl group, a tert-butoxycarbonyl group, and a sec-butoxycarbonyl group.
Examples of the xe2x80x9calkoxyoxalyl group having 3-7 carbon atomsxe2x80x9d are straight chain or branched chain alkoxyoxalyl groups, such as a methoxyoxalyl group, an ethoxyoxalyl group, an n-propoxyoxalyl group, an isopropoxyoxalyl group, an n-butoxyoxalyl group, an isobutoxyoxalyl group, a tert-butoxyoxalyl group, a sec-butoxyoxalyl group, an n-pentyloxyoxalyl group, a 3-methylbutoxyoxalyl group, and a neopentyloxyoxalyl group.
Examples of the xe2x80x9calkylamido group having 2-5 carbon atomsxe2x80x9d are straight chain or branched chain alkylamido groups, such as a methylamido group, an ethylamido group, an n-propylamido group, an isopropylamido group, an n-butylamido group, an isobutylamido group, a tert-butylamido group, a sec-butylamido group, an n-pentylamido group, and a tert-amylamido group.
Examples of the xe2x80x9calkylthio group having 1-4 carbon atomsxe2x80x9d are straight chain or branched chain alkylthio groups, such as a methylthio group, an ethylthio group, an n-propylthio group, an isopropylthio group, an n-butylthio group, an isobutylthio group, a tert-butylthio group, and a sec-butylthio group.
Examples of the xe2x80x9calkylsulfinyl group having 1-4 carbon atomsxe2x80x9d are straight chain or branched chain alkylsulfinyl groups, such as a methanesulfinyl group, an ethanesulfinyl group, an n-propylsulfinyl group, an isopropylsulfinyl group, an n-butylsulfinyl group, an isobutylsulfinyl group, a tert-butylsulfinyl group, and a sec-butylsulfinyl group.
Examples of the xe2x80x9calkylsulfamoyl group having 1-4 carbon atomsxe2x80x9d are straight chain or branched chain alkylsulfamoyl groups, such as a methanesulfamoyl group, an ethanesulfamoyl group, an n-propylsulfamoyl group, an isopropylsulfamoyl group, an n-butylsulfamoyl group, an isobutylsulfamoyl group, a tert-butylsulfamoyl group, and a sec-butylsulfamoyl group.
Examples of the xe2x80x9calkyl or alkoxy group having 1-5 carbon atoms which has been substituted by fluorine atom(s)xe2x80x9d are a trifluoromethyl group, a trifluoromethoxy group, and a tetrafluoroethoxy group.
Examples of the xe2x80x9calkylene group having 1-9 carbon atomsxe2x80x9d are a methylene group, an ethylene group, a tetramethylene group, a pentamethylene group, and a hexamethylene group.
Examples of the substituted alkylene group having 1-9 carbon atoms in the xe2x80x9calkylene group having 1-9 carbon atoms which may optionally be substitutedxe2x80x9d are a dimethylethylene group, and a monomethylethylene group.
Examples of the xe2x80x9calkoxyalkyl group having 2-5 carbon atomsxe2x80x9d are straight chain or branched chain alkoxyalkyl groups, such as a methoxymethyl group, an ethoxymethyl group, an n-propoxymethyl group, an isopropoxymethyl group, an n-butoxymethyl group, an isobutoxymethyl group, a tert-butoxymethyl group, a sec-butoxymethyl group, a methoxyethyl group, an ethoxyethyl group, an n-propoxyethyl group, an isopropoxyethyl group, a methoxypropyl group, an ethoxypropyl group, and a methoxybutyl group.
The xe2x80x9csilyl group substituted by hydrocarbon group(s)xe2x80x9d refers to a silyl group substituted, for example, by alkyl group(s) having 1-6 carbon atoms and/or aryl group(s). Examples of such a substituted silyl group are a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a dimethylisopropylsilyl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, and a triphenylsilyl group.
Examples of a case in which xe2x80x9cR3 and R7, together with the nitrogen atom to which they are bonded, form a 3- to 6-membered cyclic amino groupxe2x80x9d are pyrrolidine and piperidine.
Examples of a case in which xe2x80x9cR3 and R7, together with the nitrogen atom to which they are bonded, form a 4- to 10-membered cyclic imido groupxe2x80x9d are succinimide, phthalimide, and 1,2-cyclohexanedicarboxyimide.
Preferred modes for the compounds of the formula (I) include, for example, the following:
The preferred substitution position of R1 and R2 is the 6-position of the tetrahydroquinoline ring, and R1 and R2 are preferably such that one of them is a hydrogen atom, while the other is a nitro group or a cyano group.
X is preferably xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR7xe2x80x94, xe2x80x94NR7COxe2x80x94, xe2x80x94NR7SO2xe2x80x94, xe2x80x94NR7CONHxe2x80x94, or xe2x80x94NR7CSNHxe2x80x94 (wherein R7 is as defined earlier), more preferably xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, or xe2x80x94NR7xe2x80x94, and even more preferably xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94NR7xe2x80x94.
R7 is preferably a hydrogen atom, an alkyl group having 1-9 carbon atoms, an aralkyl group having 7-9 carbon atoms, an aryl group, or a heteroaryl group, more preferably a hydrogen atom, or an alkyl group having 1-3 carbon atoms, and even more preferably a hydrogen atom, a methyl group or an ethyl group.
R3 is preferably a hydrogen atom, an alkyl group having 1-9 carbon atoms, an aralkyl group having 7-9 carbon atoms, or an aryl or heteroaryl group which may optionally be substituted by R8 (wherein R8 represents an alkyl group having 1-9 carbon atoms, an alkoxy group having 1-9 carbon atoms, a halogen atom or a nitro group), provided that when X is NR7, R3 and R7 may, together with the nitrogen atom to which they are bonded, form a 3- to 6-membered cyclic amino group or a 4- to 10-membered cyclic imido group. More preferably, R3 is an alkyl group having 1 -3 carbon atoms, an aralkyl group having 7-9 carbon atoms, or an aryl group, and even more preferably, R3 is a methyl group or an ethyl group.
In the definition of Y, the number of the substituents which may optionally take part in substitution is preferably 1 to 3, and preferred examples of the substituent are a methyl group and an ethyl group.
Y is preferably an alkylene group having 1-9 carbon atoms that may optionally be substituted by alkyl group(s) having 1-9 carbon atoms, more preferably an alkylene group having 1-4 carbon atoms that may optionally be substituted by alkyl group(s) having 1-2 carbon atoms, further preferably a dimethylethylene or monomethylethylene group, and still further preferably xe2x80x94C(CH3)2xe2x80x94CH2xe2x80x94.
ZR4 is preferably such that when Z is xe2x80x94Oxe2x80x94, xe2x80x94OCOxe2x80x94, xe2x80x94OSO2xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NHCOxe2x80x94, xe2x80x94NHSO2xe2x80x94, xe2x80x94NHCONHxe2x80x94, xe2x80x94NHCSNHxe2x80x94, or xe2x80x94NHCOOxe2x80x94, R4 is a hydrogen atom, an alkyl group having 1-9 carbon atoms, an aralkyl group having 7-9 carbon atoms, an alkoxyalkyl group having 2-5 carbon atoms, a silyl group substituted by hydrocarbon group(s), or an aryl or heteroaryl group which may optionally be substituted by R15 (wherein R15 is as defined previously). More preferably, ZR4 is such that when Z is xe2x80x94Oxe2x80x94 or xe2x80x94OCOxe2x80x94, R4 is a hydrogen atom, an alkyl group having 1-4 carbon atoms, or an aryl group which may optionally be substituted by R15. Even more preferably, ZR4 is a hydroxyl group.
In this case, R15 is preferably an alkyl group having 1-9 carbon atoms, an alkoxy group having 1-9 carbon atoms, a halogen atom, or an acetamido group, and more preferably a halogen atom or an acetamido group.
Preferred combinations of the substituents in the formula (I) are such that R1 is a nitro group or a cyano group; R2 is a hydrogen atom; X is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR7xe2x80x94, xe2x80x94NR7COxe2x80x94, xe2x80x94NR7SO2xe2x80x94, xe2x80x94NR7CONHxe2x80x94, or xe2x80x94NR7CSNHxe2x80x94 (wherein R7 is preferably a hydrogen atom, an alkyl group having 1-9 carbon atoms, an aralkyl group having 7-9 carbon atoms, an aryl group, or a heteroaryl group); R3 is a hydrogen atom, an alkyl group having 1-9 carbon atoms, an aralkyl group having 7-9 carbon atoms, or an aryl or heteroaryl group which may optionally be substituted by R8 (wherein R8 is an alkyl group having 1-9 carbon atoms, an alkoxy group having 1-9 carbon atoms, a halogen atom or a nitro group), provided that when X is NR7, R3 and R7 may, together with the nitrogen atom to which they are bonded, form a 3- to 6-membered cyclic amino group or a 4- to 10-membered cyclic imido group; Y is an alkylene group having 1-9 carbon atoms that may optionally be substituted by alkyl group(s) having 1-9 carbon atoms; Z is xe2x80x94Oxe2x80x94, xe2x80x94OCOxe2x80x94, xe2x80x94OSO2, xe2x80x94NHxe2x80x94, xe2x80x94NHCOxe2x80x94, xe2x80x94NHSO2xe2x80x94, xe2x80x94NHCONHxe2x80x94, xe2x80x94NHCSNHxe2x80x94, or xe2x80x94NHCOOxe2x80x94; R4 is a hydrogen atom, an alkyl group having 1-9 carbon atoms, an aralkyl group having 7-9 carbon atoms, an alkoxyalkyl group having 2-5 carbon atoms, a silyl group substituted by hydrocarbon group(s), or an aryl or heteroaryl group that may optionally be substituted by R15 (wherein R15 is an alkyl group having 1-9 carbon atoms, an alkoxy group having 1-9 carbon atoms, a halogen atom, or an acetamido group).
More preferred combinations are such that R1 is a nitro group or a cyano group; R2 is a hydrogen atom; X is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, or xe2x80x94NR7xe2x80x94 (wherein R7 is preferably a hydrogen atom, or an alkyl group having 1-3 carbon atoms); R3 is an alkyl group having 1-3 carbon atoms, an aralkyl group having 7-9 carbon atoms, or an aryl group; Y is an alkylene group having 1-4 carbon atoms that may optionally be substituted by alkyl group(s) having 1-2 carbon atoms; Z is xe2x80x94Oxe2x80x94 or xe2x80x94OCOxe2x80x94; R4 is a hydrogen atom, an alkyl group having 1-4 carbon atoms, or an aryl group that may optionally be substituted by R15 (wherein R15 is preferably a halogen atom or an acetamido group).
The most preferred combinations are such that R1 is a nitro group or a cyano group; R2 is a hydrogen atom; X is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94NR7xe2x80x94 (wherein R7 is preferably a hydrogen atom, a methyl group or an ethyl group); R3 is a methyl group or an ethyl group; Y is a dimethylethylene group or a monomethylethylene group; and ZR4 is a hydroxyl group.
Particularly preferred compounds of the present invention are as follows:
2-(4-Ethoxy-6-nitro-1,2,3,4-tetrahydroquinolin-2-yl)-2-methylpropan-1-ol (Example 3)
2-(4-Ethylsulfanyl-6-nitro-1,2,3,4-tetrahydroquinolin-2-yl)-2-methylpropan-1-ol (Example 4)
2-Methyl-2-(6-nitro-4-phenylsulfanyl-1,2,3,4-tetrahydroquinolin-2-yl)propan-1-ol (Example 5)
Acetic acid 2-(4-dimethylamino-6-nitro-1,2,3,4-tetrahydroquinolin-2-yl)-2-methyl-propyl ester (Example 9)
4-Fluorobenzoic acid 2-(4-dimethylamino-6-nitro-1,2,3,4-tetrahydroquinolin-2-yl)-2-methyl-propyl ester (Example 11)
2-(4-Dimethylamino-6-nitro-1,2,3,4-tetrahydroquinolin-2-yl)-2-methylpropan-1-ol (Example 23)
2-(4-Benzylamino-6-nitro-1,2,3,4-tetrahydroquinolin-2-yl)-2-methylpropan-1-ol (Example 30)
2-(4-Di-n-propylamino-6-nitro-1,2,3,4-tetrahydroquinolin-2-yl)-2-methylpropan-1-ol (Example 33)
If asymmetric carbon is present in the compound of the present invention represented by the formula (I), its racemic compounds, diastereomers, and individual optical isomers are all included in the present invention. If its geometrical isomers are present, (E) compounds, (Z) compounds, and mixtures of them are all included in the present invention.
The salts of the compounds of the present invention represented by the formula (I) are not limited, as long as they are those which are pharmacologically acceptable. Their examples include hydrohalogenic acid salts, such as hydrofluorides, hydrochlorides, hydrobromides, and hydroiodides, inorganic acid salts, such as nitrates, perchlorates, sulfates, phosphates, and carbonates, lower alkylsulfonic acid salts, such as methanesulfonates, trifluoromethanesulfonates, and ethanesulfonates, arylsulfonic acid salts, such as benzenesulfonates and p-toluenesulfonates, carboxylic acid salts, such as acetates, fumarates, succinates, citrates, tartrates, oxalates, and maleates, amino acid salts, such as glycine salts, alanine salts, glutamates, and aspartates, and alkali metal salts, such as sodium salts and potassium salts.
Solvates of the compounds of the present invention are also included in the present invention. Examples of the solvates are solvates with solvents, such as acetone, 2-butanol, 2-propanol, ethanol, ethyl acetate, tetrahydrofuran, and diethyl ether.
The tetrahydroquinoline compounds of the present invention can be produced by the following methods:
[Production Method 1]
where all the symbols are as defined above, except for a case where xe2x80x94Xxe2x80x94R3 represents NH2, and cases where -Z-R4 represents SH, SOR4, SO2R4 or NH2.
The compound of the present invention, expressed by the formula (I), can be produced by reacting the compounds represented by the formulas (a), (b) and (c) in an inert solvent in the presence or absence of an acid.
The compounds represented by the formulas (a), (b) and (c) can be obtained as commercially available reagents, or by easy derivation therefrom by routine chemical reactions.
The present reaction will be described concretely. Any type of acids, organic or inorganic, are preferred. For example, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, tin tetrachloride, titanium tetrachloride, boron trifluoride diethyl etherate, diethylaluminum chloride, or ethylaluminum dichloride is used. The acid is preferably used in an amount of a catalytic amount to 10 equivalents with respect to the compound represented by the formula (a). The reaction solvent is not limited, as long as it is a solvent which does not markedly impede the present reaction. The preferred reaction solvent is dichloromethane, chloroform, 1,2-dichloroethane, hexane, benzene, toluene, dioxane, tetrahydrofuran, acetonitrile, methanol, ethanol, water or a mixture of these solvents. The reaction temperature is preferably xe2x88x9220 to 100xc2x0 C., and the reaction time is preferably 5 minutes to 48 hours.
[Production Method 2]
where TBDPS signifies a tert-butyldiphenylsilyl group, and the other symbols are as defined earlier.
Of the compounds of the present invention, the compound represented by the formula (Ib) can be produced by deprotection of the compound represented by the formula (Ia) by means of hydrolysis in the presence of an acid or a base or treatment with a fluoride, in addition to the method shown in Production Method 1.
The present reaction will be described concretely. Any type of acids, organic or inorganic, are preferred. For example, acetic acid, trifluoroacetic acid, hydrochloric acid, or sulfuric acid is used. Either type of bases, metal hydroxides or metal carbonates, are preferred. For example, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, or potassium carbonate is used. As the fluoride, an aqueous hydrogen fluoride solution, or tetrabutylammonium fluoride, for example, is used. The acid, base or fluoride is preferably used in an amount of 1 to 50 equivalents with respect to the compound represented by the formula (Ia). The reaction solvent is not limited, as long as it is a solvent which does not markedly impede the present reaction. The preferred reaction solvent is dichloromethane, chloroform, 1,2-dichloroethane, hexane, benzene, toluene, dioxane, tetrahydrofuran, acetonitrile, methanol, ethanol, water or a mixture of these solvents. The reaction temperature is preferably xe2x88x9240 to 100xc2x0 C., and the reaction time is preferably 30 minutes to 24 hours.
[Production Method 3]
where D represents a halogen atom, a chlorosulfonyl group or a halogenated carbonyl group, Z1 represents xe2x80x94Oxe2x80x94, xe2x80x94OCOxe2x80x94 or xe2x80x94OSO2xe2x80x94, and the other symbols are as defined earlier, except for a case where xe2x80x94Xxe2x80x94R3 is NH2.
Of the compounds of the present invention, the compound represented by the formula (Ic) can be produced by reacting the compound represented by the formula (Ib) with the compound represented by the formula (d) or (dxe2x80x2) without a solvent or in an inert solvent in the presence or absence of a base.
The compounds represented by the formulas (d) and (dxe2x80x2) can be obtained as commercially available reagents, or by easy derivation therefrom by routine chemical reactions.
Examples of the xe2x80x9chalogenated carbonyl groupxe2x80x9d are a chlorocarbonyl group and a bromocarbonyl group.
The present reaction will be described concretely. The base is preferably a tertiary amine, and its examples are triethylamine and pyridine. The compound represented by the formula (d) or (dxe2x80x2) is preferably used in an amount of 1 to 10 equivalents with respect to the compound represented by the formula (Ib). The base is preferably used in an amount of 1 equivalent to a large excess with respect to the compound represented by the formula (d) or (dxe2x80x2). The reaction solvent is not limited, as long as it is a solvent which does not markedly impede the present reaction. The preferred reaction solvent is dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, toluene, dimethylformamide, or tetrahydrofuran. The reaction temperature is preferably 0 to 80xc2x0 C., and the reaction time is preferably 30 minutes to 12 hours.
[Production Method 4]
where Boc represents a tert-butoxycarbonyl group, and the other symbols are as defined earlier.
Of the compounds of the present invention, the compound represented by the formula (Ie) can be produced by deprotection of the compound represented by the formula (Id) by means of treatment with an acid.
The present reaction will be described concretely. Any type of acids, organic or inorganic, are preferred. For example, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, or sulfuric acid is used. The acid is preferably used in an amount of 1 to 50 equivalents with respect to the compound represented by the formula (Id). The reaction solvent is not limited, as long as it is a solvent which does not markedly impede the present reaction. The preferred reaction solvent is dichloromethane, chloroform, 1,2-dichloroethane, hexane, benzene, toluene, dioxane, tetrahydrofuran, acetonitrile, methanol, ethanol, water, or a mixture of these solvents. The reaction temperature is preferably 0 to 100xc2x0 C., and the reaction time is preferably 30 minutes to 24 hours.
[Production Method 5]
where E represents a chlorosulfonyl group, a halogenated carbonyl group, an isocyanato group, or a thioisocyanato group, Z2 represents xe2x80x94NHCOxe2x80x94, xe2x80x94NHSO2xe2x80x94, xe2x80x94NHCONHxe2x80x94, or xe2x80x94NHCSNHxe2x80x94, and the other symbols are as defined earlier, except for a case where xe2x80x94Xxe2x80x94R3 is NH2.
Of the compounds of the present invention, the compound represented by the formula (If) can be produced by reacting the compound represented by the formula (Ie) with the compound represented by the formula (e) or (dxe2x80x2) without a solvent or in an inert solvent in the presence or absence of a base.
The compound represented by the formula (e) can be obtained as a commercially available reagent, or by easy derivation therefrom by routine chemical reactions.
Examples of the xe2x80x9chalogenated carbonyl groupxe2x80x9d are a chlorocarbonyl group and a bromocarbonyl group.
The present reaction will be described concretely. The base is preferably a tertiary amine, and its examples are triethylamine and pyridine. The compound represented by the formula (e) or (dxe2x80x2) is preferably used in an amount of 1 to 10 equivalents with respect to the compound represented by the formula (Ie). The base is preferably used in an amount of 1 equivalent to a large excess with respect to the compound represented by the formula (e) or (dxe2x80x2). The reaction solvent is not limited, as long as it is a solvent which does not markedly impede the present reaction. The preferred reaction solvent is dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, toluene, dimethylformamide, or tetrahydrofuran. The reaction temperature is preferably 0 to 80xc2x0 C., and the reaction time is preferably 30 minutes to 24 hours.
[Production Method 6]
where Z3 represents a single bond, R4xe2x80x2 represents a halogen atom, R4xe2x80x3 represents R4 other than a halogen atom, and the other symbols are as defined earlier.
Of the compounds of the present invention, the compound represented by the formula (Ih) can be produced by reacting the compound represented by the formula (Ig) with the compound represented by the formula (f) without a solvent or in an inert solvent in the presence or absence of a base.
The compound represented by the formula (f) can be obtained as a commercially available reagent, or by easy derivation therefrom by routine chemical reactions.
The present reaction will be described concretely. The base is, for example, triethylamine, pyridine, sodium hydride, or potassium tert-butoxide. The compound represented by the formula (f) is preferably used in an amount of 1 to 10 equivalents with respect to the compound represented by the formula (Ig). The base is preferably used in an amount of 1 equivalent to a large excess with respect to the compound represented by the formula (f). The reaction solvent is not limited, as long as it is a solvent which does not markedly impede the present reaction. The preferred reaction solvent is dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, toluene, dimethylformamide, or tetrahydrofuran. The reaction temperature is preferably 0 to 100xc2x0 C., and the reaction time is preferably 5 minutes to 24 hours.
[Production Method 7]
where Z4 represents xe2x80x94SOxe2x80x94 or xe2x80x94SO2xe2x80x94, and the other symbols are as defined earlier, except for a case where X is xe2x80x94Sxe2x80x94 or xe2x80x94SOxe2x80x94.
Of the compounds of the present invention, the compound represented by the formula (Ii) can be produced by oxidizing the compound represented by the formula (Ih) in an inert solvent in the presence of an oxidizing agent.
The present reaction will be described concretely. As the oxidizing agent, peracetic acid or m-chloroperbenzoic acid, for example, is named. The oxidizing agent is preferably used in an amount of 1 equivalent to a large excess with respect to the compound represented by the formula (Ih). The reaction solvent is not limited, as long as it is a solvent which does not markedly impede the present reaction. The preferred reaction solvent is dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, toluene, dimethylformamide, or tetrahydrofuran. The reaction temperature is preferably xe2x88x9220 to 100xc2x0 C., and the reaction time is preferably 5 minutes to 24 hours.
[Production Method 8]
where all the symbols are as defined earlier.
Of the compounds of the present invention, the compound represented by the formula (Ik) can be produced by hydrolyzing the compound represented by the formula (Ij) in the usual manner in the presence of an acid or a base.
The present reaction will be described concretely. Any type of acids, organic or inorganic, are preferred. For example, acetic acid, trifluoroacetic acid, hydrochloric acid, or sulfuric acid is named. Either type of bases, metal hydroxides or metal carbonates, are preferred. For example; sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, or potassium carbonate is named. The acid or base is preferably used in an amount of 1 to 50 equivalents with respect to the compound represented by the formula (Ij). The reaction solvent is not limited, as long as it is a solvent which does not markedly impede the present reaction. The preferred reaction solvent is water, methanol, ethanol, tetrahydrofuran, dioxane, chloroform, 1,2-dichloroethane, or a mixture of these solvents. The reaction temperature is preferably 0 to 100xc2x0 C., and the reaction time is preferably 30 minutes to 24 hours.
[Production Method 9]
where all the symbols are as defined earlier.
Of the compounds of the present invention, the compound represented by the formula (In) can be produced by deprotection of the compound represented by the formula (Im) by means of hydrolysis in the presence of an acid or a base, or catalytic reduction in the presence of a catalyst.
The present reaction will be described concretely. Any type of acids, organic or inorganic, are preferred. For example, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, or sulfuric acid is named. Either type of bases, organic bases or inorganic bases, are preferred. For example, methylhydrazine or sodium hydroxide is named. The acid or base is preferably used in an amount of 1 equivalent to a large excess with respect to the compound represented by the formula (Im). The catalyst used in the catalytic reduction reaction is, for example, 5% palladium carbon or 10% palladium carbon. The catalyst is preferably used in an amount of a catalytic amount to 10 equivalents with respect to the compound represented by the formula (Im). The hydrogen pressure is preferably 1 to 5 atmospheres. The reaction solvent is not limited, as long as it is a solvent which does not markedly impede the present reaction. The preferred reaction solvent is dichloromethane, chloroform, 1,2-dichloroethane, hexane, benzene, toluene, dioxane, tetrahydrofuran, acetonitrile, methanol, ethanol, water, or a mixture of these solvents. The reaction temperature is preferably 0 to 100xc2x0 C., and the reaction time is preferably 30 minutes to 48 hours.
[Production Method 10]
where X2 represents xe2x80x94NHCOxe2x80x94, xe2x80x94NHSO2xe2x80x94, xe2x80x94NHCONHxe2x80x94, or xe2x80x94NHCSNHxe2x80x94, and the other symbols are as defined earlier, except for a case where -Z-R4 is NH2.
Of the compounds of the present invention, the compound represented by the formula (Io) can be produced by reacting the compound represented by the formula (In) with the compound represented by the formula (g) or (gxe2x80x2) without a solvent or in an inert solvent in the presence or absence of a base.
The compounds represented by the formulas (g) and (gxe2x80x2) can be obtained as commercially available reagents, or by easy derivation therefrom by routine chemical reactions.
The reaction conditions for the present reaction can be set in the same manner as in Production Method 5.
[Production Method 11]
where R3 represents a hydrogen atom, an alkyl group having 1-8 carbon atoms, an aralkyl group having 7-8 carbon atoms, an alkoxyalkyl group having 2-4 carbon atoms, or an aryl group, R7xe2x80x2 represents a hydrogen atom, an alkyl group having 1-8 carbon atoms, an aralkyl group having 7-8 carbon atoms, an alkoxyalkyl group having 2-4 carbon atoms, or an aryl group, and the other symbols are as defined earlier, except for a case where -Z-R4 is NH2.
Of the compounds of the present invention, the compounds represented by the formulas (Ip) and (Iq) can be produced by the reductive amination of the compound represented by the formula (In) with the compounds represented by the formulas (h) and (i) in the usual manner without a solvent or in an inert solvent in the presence or absence of an acid.
The compounds represented by the formulas (h) and (i) can be obtained as commercially available reagents, or by easy derivation therefrom by routine chemical reactions.
The present reaction will be described concretely. Any type of acids, organic or inorganic, are preferred. For example, formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, or sulfuric acid is named. As the reducing agent, inorganic metallic reagents or organic metallic reagents are preferred. Examples include palladium, zinc, sodium cyanoborohydride, sodium triacetoxyborohydride, and aluminum lithium hydride. The compound represented by the formula (h) or (i) is preferably used in an amount of 1 equivalent to an excess with respect to the compound represented by the formula (In) or (Ip), respectively. Particularly, the compound of the formula (Iq), in which R3 and R7 are the same, can be produced in a single step by using an excess of the compound represented by the formula (h). The acid or base is preferably used in an amount of 1 equivalent to a large excess with respect to the compound represented by the formula (In) or (Ip). The reaction solvent is not limited, as long as it is a solvent which does not markedly impede the present reaction. The preferred reaction solvent is methanol, ethanol, tetrahydrofuran, dioxane, chloroform, 1,2-dichloroethane, or a mixture of these solvents. The reaction temperature is preferably xe2x88x9278 to 100xc2x0 C., and the reaction time is preferably 30 minutes to 24 hours.
[Production Method 12]
where X4 represents xe2x80x94SOxe2x80x94 or xe2x80x94SO2, and the other symbols are as defined earlier, except for a case where Z is xe2x80x94Sxe2x80x94 or xe2x80x94SOxe2x80x94.
Of the compounds of the present invention, the compound represented by the formula (Is) can be produced by oxidizing the compound represented by the formula (Ir) in an inert solvent in the presence of an oxidizing agent.
The reaction conditions for the present reaction can be set in the same manner as in Production Method 7.
The compounds of the present invention, which are produced by the above-described methods, are isolated and purified as free compounds, their salts, their hydrates, various solvates thereof, such as ethanolates, or crystalline polymorphic substances. The pharmacologically acceptable salts of the compounds according to the present invention can be produced by the general salt-forming reaction. The isolation and purification are performed by applying chemical operations, such as extractive fractionation, crystallization, and various chromatographic techniques. The stereochemically pure optical isomers can be synthesized by using suitable starting compounds, or by optical resolution of racemic compounds.
The tetrahydroquinoline compounds or pharmacologically acceptable salts thereof according to the present invention have an excellent AR modulating action. These substances can be used as active ingredients to form pharmaceuticals or AR modulators. These pharmaceuticals can be widely used in the prophylaxis or treatment of various AR-related diseases.
As the AR-related diseases, the following categories A and B are named:
A. Diseases which can be expected to be cured by the physiological action of androgen: Examples include male hypogonadism, male sexual dysfunction (impotence, male dysspermatogenic sterility), abnormal sex differentiation (male hermaphroditism), male delayed puberty, male infertility, aplastic anemia, hemolytic anemia, sickle cell anemia, idiopathic thrombocytopenic purpura, myelofibrosis, renal anemia, wasting diseases (after operation, malignant tumor, trauma, chronic renal disease, burns, AIDS infection), osteoporosis, abatement of pain in terminal carcinoma of female genitalia, inoperable breast cancer, mastopathy, endometriosis, and female sexual dysfunction.
The tetrahydroquinoline compounds or pharmacologically acceptable salts thereof according to the present invention show a particularly potent action on bone tissues and skeletal muscles. Thus, they are suggested to have a protein anabolic action, and can be used in the prophylaxis or treatment of the diseases described below.
Diseases for which they may be indicated because of their potent action on bone tissues include, for example, primary osteoporosis (senile, postmenopausal and juvenile osteoporosis) and secondary osteoporosis (osteoporosis ascribed to hyperthyroidism, Cushing syndrome (due to steroid treatment), acromegaly, hypogonadism, dysosteogenesis, hypophosphatasemia, osteoporosis of disuse, or diabetes).
Diseases for which they may be indicated because of their potent action on muscular tissues include, for example, wasting diseases (after operation, malignant tumor, trauma, chronic renal disease, burns, AIDS infection).
B. Diseases for which androgen is a precipitating factor: Examples include prostatic cancer, prostatomegaly, virilization, acne, seborrhea, hypertrichosis, alopecia, male precocious puberty, and polycystic ovary syndrome.
For the category A diseases, the compounds of the present invention with AR agonistic action can be used, their preferred examples being compounds of Examples 3, 4, 5, 23 and 30 to be described later.
For the category B diseases, the compounds of the present invention with AR antagonistic action can be used. For example, a compound of Example 33 to be described later was suggested by a Test Example (to be described later) to be an AR antagonist.
The pharmaceuticals of the present invention can be applied widely to these AR-related diseases, and may be applied to diseases which are not exemplified here, if the modulation of AR function is required for them at present or in the future.
The pharmaceuticals of the present invention can be administered orally or parenterally, and may be of the systemic administration type or local administration type.
Their dosage forms are not limited, and can be selected, as desired, according to the route of administration. Their examples include tablets, capsules, sugar-coated tablets, granules, subtle granules, inhalations, suppositories, liquids and solutions, syrups, dry syrups, suspensions, emulsions, lotions, ointments, patches, sprays, gels, nasal drops, eye drops, and injections.
These preparations can be produced by incorporating pharmacologically acceptable carriers, namely, organic or inorganic, solid or liquid vehicles, adjuvants, stabilizers, wetting agents, emulsifying agents, buffers, and other pharmacologically acceptable various additives, into compositions containing the compounds of the present invention.
The dose of the pharmaceutical of the present invention in humans is determined, as desired, according to various conditions, such as the purpose of treatment or prevention, the patient""s sex, body weight, and age, the type and severity of the disease, dosage form, the route of administration, and the duration of treatment. The daily dose of the tetrahydroquinoline compound of the present invention is generally 0.01 to 100 mg/kg.
The pharmaceuticals of the present invention may be used in the treatment of androgen receptor-mediated diseases in warm-blooded animals, such as domestic animals, pets, bred animals, or wild animals. The dosage forms and doses in this case can be determined by reference to the dosage forms and doses in humans.